Leishmaniasis is a protozoan parasitic disease endemic in 88 countries, which causes considerable morbidity and mortality. At least 20 species of Leishmania can be transmitted by sandfly bites, originating cutaneous, diffuse cutaneous, mucocutaneous and visceral leishmaniasis in humans, dogs and various wild vertebrate hosts. The estimated yearly incidence is 1-1.5 million cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis. The population at risk is estimated at 350 million people with an overall prevalence of 12 million. Increasing risk factors are making leishmaniasis a growing public health concern for many countries around the world.
The drugs most commonly used to treat leishmaniasis are the pentavalent antimonials sodium stibogluconate (Pentostam) and meglumine antimonate (Glucantime). Antimonial chemotherapy requires high dose regimens with long treatment courses using parenteral administration. Second-line drugs, used in instances of antimonial-treatment failure, include amphotericin B (AMB), paromomycin (aminosidine), and pentamidine. However, all of these drugs are far from satisfactory due to unacceptable side effects at effective doses. The recently developed liposomal formulation of amphotericin B (AmBisome™) showed good curative rates for antimony unresponsive cases of mucocutaneous leishmaniasis however, drug administration is technically difficult and treatment costs are prohibitively expensive.
The spreading resistance of the parasite towards the standby antimonial drugs, the high toxicity of most drugs in use, and the emergence of Leishmania/HIV co-infection as a new disease entity has triggered a continuous search for alternative therapies. Visceral leishmaniasis caused by L. infantum has emerged as an AIDS-associated opportunistic infection, particularly in southern Europe.
In recent years, alkyllysophospholipid analogues (ALPs) have received considerable interest due to their antineoplastic and immunomodulatory properties. Extensive structure-activity relationship studies on a variety of ALPs showed that a long alkyl chain and a phosphocholine moiety may represent the minimal structural requirements for sufficient antineoplastic effects of ether lipid analogues. This finding led to the synthesis of the alkylphosphocholines (APCs). Within the alkyl chain homologs, hexadecylphosphocholine (HePC) has therapeutically useful antitumor activity and was approved in 1992 as a drug in Germany for the topical treatment of metastasized mammary carcinoma.
Several in vitro and in vivo studies demonstrated that alkylphosphocholines including HePC, and alkylglycerophosphocholines such as edelfosine, ilmofosine and SRI-62,834 possess antileishmanial activity. Hexadecylphosphocholine was reported to be highly effective in treating mice infected with visceral leishmaniasis while oral treatment with miltefosine was 600-fold more effective than the subcutaneous administration of pentostam. On the basis of these promising observations HePC (miltefosine) was evaluated in phase I and II clinical trials as oral therapy for Indian visceral leishmaniasis while phase III clinical trials are currently ongoing. Cure rates of 88% to 100% were obtained using doses of 100-150 mg/day for 28 days. These results encouraged studies on the efficacy of miltefosine treatment for cutaneous leishmaniasis in the New World and currently phase II studies are being conducted. In a phase I study, the cure rate with miltefosine at doses of 100-150 mg for 3 weeks was 94%. In the various clinical trials, the main side effects associated with miltefosine were gastrointestinal with the most common being moderate vomiting and diarrhea. Transient elevation of transaminases or urea/serum creatinine was noted in a number of patients and decreased under continued treatment. Although the toxicity associated with miltefosine sounds milder than that of some parenteral therapies, gastrointestinal symptoms could be of more consequence in severely ill patients, such as those who are malnourished or dehydrated. In addition, treatment of pregnant women is contraindicated because of miltefosine's teratogenic properties in animals. Furthermore, miltefosine has a very long half-life and low therapeutic ratio and a course of treatment leaves a sub-therapeutic level in the blood for several weeks. These drug characteristics might be expected to encourage development of resistance. Additionally, miltefosine was shown to be only temporarily effective in HIV co-infected patients in Europe. Therefore, a need exists for new phospholipids in the treatment of protozoal diseases and especially leishmaniasis that will not cause significant adverse side effects.
U.S. Pat. No. 5,436,234 discloses compounds of the general formula:R—X-A-PO3—(CH2)2—N+R1R2R3 Wherein R is a erucyl, brassidyl or nervonyl radical, R1, R2 and R3 are, independently of one another, straight-chained, branched or cyclic saturated or unsaturated alkyl radicals containing up to 4 carbon atoms, which can also contain a hydroxyl group, and wherein two of these radicals can also be connected together to form a ring, A is a valency bond or a radical of one of the formulae:
And X is an oxygen atom when A is preferably a valency bond. Compounds of the general formula R—X-A-PO3—(CH2)2—N+R1R2R3 and pharmaceutical compositions containing them can be used for the treatment of protozoal and fungal diseases, autoimmune diseases and bone marrow damage.
U.S. Pat. No. 6,254,879 which is continuation-in part of application Ser. No. 08/469,779 now U.S. Pat. No. 5,980,915 discloses a new pharmaceutical agent for oral or topical administration in the treatment of protozoal diseases, in particular of leishmaniasis which contains as the active substance one or several compounds of the general formulaR1—PO4—CH2CH2—N+R2R3R4 in which R1 is a saturated or monounsaturated or polyunsaturated hydrocarbon residue with 12 to 20 C atoms.
U.S. Pat. No. 6,344,576 relates to phosphor-lipid compounds of formula (I)
having solubilizing activity for water-insoluble or poorly water soluble active agents and their use in the delivery of active agents to cells and in the treatment of diseases, i.e. cancer and protozoal diseases.in which A
where R1 and R2 are, independently of one another, hydrogen, a saturated or unsaturated acyl or alkyl radical which can optionally be branched or/and substituted, where the total of the carbon atoms in the acyl and alkyl is 16 to 44 C atoms.